The novel β-secretase inhibitor KMI-429 reduces amyloid β peptide production in amyloid precursor protein transgenic and wild-type mice

Authors

  • Masashi Asai,

    1. Department of Life Sciences, Graduate School of Arts and Sciences, University of Tokyo, Tokyo, Japan
    2. Laboratory for Proteolytic Neuroscience, RIKEN Brain Science Institute, Saitama, Japan
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    • 1

      The present address of Masashi Asai is Department of Pharmacology, Saitama Medical School, 38 Moro-hongo, Moroyama-cho, Iruma-gun, Saitama 350–0495, Japan.

  • Chinatsu Hattori,

    1. Department of Life Sciences, Graduate School of Arts and Sciences, University of Tokyo, Tokyo, Japan
    2. Glyco-chain Functions Laboratory, Supra-biomolecular System Group, Frontier Research System, RIKEN, Saitama, Japan
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  • Nobuhisa Iwata,

    1. Laboratory for Proteolytic Neuroscience, RIKEN Brain Science Institute, Saitama, Japan
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  • Takaomi C. Saido,

    1. Laboratory for Proteolytic Neuroscience, RIKEN Brain Science Institute, Saitama, Japan
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  • Noboru Sasagawa,

    1. Department of Life Sciences, Graduate School of Arts and Sciences, University of Tokyo, Tokyo, Japan
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  • Beáta Szabó,

    1. Department of Life Sciences, Graduate School of Arts and Sciences, University of Tokyo, Tokyo, Japan
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  • Yasuhiro Hashimoto,

    1. Glyco-chain Functions Laboratory, Supra-biomolecular System Group, Frontier Research System, RIKEN, Saitama, Japan
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  • Kei Maruyama,

    1. Department of Pharmacology, Saitama Medical School, Saitama, Japan
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  • Sei-ichi Tanuma,

    1. Department of Biochemistry, Faculty of Pharmaceutical Sciences, Tokyo University of Science, Chiba, Japan
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  • Yoshiaki Kiso,

    1. Department of Medicinal Chemistry, Center of Frontier Research in Medicinal Science and 21st Century COE (Center of Excellence) Program, Kyoto Pharmaceutical University, Kyoto, Japan
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  • Shoichi Ishiura

    1. Department of Life Sciences, Graduate School of Arts and Sciences, University of Tokyo, Tokyo, Japan
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Address correspondence and reprint requests to Professor Shoichi Ishiura, Department of Life Sciences, Graduate School of Arts and Sciences, University of Tokyo, 3-8-1 Komaba, Meguro-ku, Tokyo 153–8902, Japan. E-mail: cishiura@mail.ecc.u-tokyo.ac.jp

Abstract

Alzheimer's disease (AD) is a neurodegenerative disorder characterized by the accumulation of amyloid plaques and neurofibrillary tangles in the brain. The major component of the plaques, amyloid β peptide (Aβ), is generated from amyloid precursor protein (APP) by β- and γ-secretase-mediated cleavage. Because β-secretase/beta-site APP cleaving enzyme 1 (BACE1) knockout mice produce much less Aβ and grow normally, a β-secretase inhibitor is thought to be one of the most attractive targets for the development of therapeutic interventions for AD without apparent side-effects. Here, we report the in vivo inhibitory effects of a novel β-secretase inhibitor, KMI-429, a transition-state mimic, which effectively inhibits β-secretase activity in cultured cells in a dose-dependent manner. We injected KMI-429 into the hippocampus of APP transgenic mice. KMI-429 significantly reduced Aβ production in vivo in the soluble fraction compared with vehicle, but the level of Aβ in the insoluble fraction was unaffected. In contrast, an intrahippocampal injection of KMI-429 in wild-type mice remarkably reduced Aβ production in both the soluble and insoluble fractions. Our results indicate that the β-secretase inhibitor KMI-429 is a promising candidate for the treatment of AD.

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